Welcome, everyone. I'm Joe Schwartz from the Leerink Partners Biotech Equity Research Team, and it's my pleasure to host.
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Host with the microphone.
Welcome, everyone. There we go. My pleasure to host this fireside chat with Gossamer. I'm Joe Schwartz from the Biotech Equity Research Team at Leerink Partners, and today we are very pleased to have Bryan Giraudo, Chief Operating Officer, and Robert Roscigno, Clinical Development for Pulmonary Disease from the company. Maybe we can start, Bryan, by having you give us a high-level set excuse me, just to make sure we bring everyone up to the same level, same knowledge base here, given how important this year is for Gossamer and how we can look forward to some good things, hopefully before the end of the year.
Absolutely. First and foremost, thank you for having us, Joe. It's always a pleasure to be at a Leerink event, especially your signature conference. Thank you very much. It is a very important year for us at Gossamer. We will have the results of our phase III registrational study for pulmonary hypertension, the PROSERA study. We expect to complete enrollment in the second quarter of this year with top-line data in the fourth quarter. Obviously, this is where we have put almost all the resources of the company to be able to turn this card with a march towards registration and a 2027 launch. We will also be commencing a phase III registrational study in PH-ILD, or pulmonary hypertension associated with interstitial lung disease.
We expect that study to get up and running in the second half of the year, with our first patient to be enrolled most likely early in the fourth quarter. A very, very exciting time at the company, one where we are working diligently to make sure that we have not only the right patient profile in the PROSERA study, but one that will allow us to take advantage of a very, very rapidly evolving competitive landscape as far as not only the treatment algorithm going forward, but a variety of treatments that we think will make the patient journey a heck of a lot better.
Great. There are a lot of things we can dive into there. Maybe we'll start with the competitive landscape, just since you mentioned it.
Sure.
Something we've been wondering about a lot. We just commissioned a survey and found that there's still some unmet need. I'd love to hear your thoughts from the company perspective, what this looks like to you, assuming seralutinib succeeds, what kind of a treatment landscape it could be entering.
I think we have to start with those programs that were behind us in development, specifically the TROPOS study from Keros, which had a similar mechanism of action to the Merck drug sotatercept, Winrevair, activin ligand trap. Unfortunately, that study was discontinued. It was a phase II study because of some adverse events. We'll come back to it. They saw elevations of pericardial effusion, which is obviously not a very good thing. We also had a close competitor with a company called Aerovate with inhaled imatinib. That drug, in a phase II-B study, did not show statistically significant efficacy. For those therapies that were on our heels, there really is nothing. We're the only company that is pursuing a phase III study in pulmonary hypertension.
What's in front of us is Merck's drug, sotatercept or Winrevair, a very good therapy, but not one that is without its liabilities when it comes to both safety, efficacy, and durability of treatment. Certainly, we continue to see an increase in reports of serious adverse events, which when we compare it to seralutinib's clinical experience to date, I think we can certainly say that we have best-in-class safety, and we hope to have best-in-class efficacy as well. What that has really created is a very significant opportunity for a therapy like seralutinib that will bring not only, we believe, best-in-class durability and efficacy, but with safety, we can keep patients on for a very, very long time.
I think the sotatercept experience to date with their launch in the United States and now in Germany is demonstrating that in this fragile patient population, safety is really, really important. We're starting to get a real transparent view into this real time in the United States because, as you know, Joe, as part of our phase III protocol, we allow patients that meet our entry criteria if they're on background sotatercept to come into the study, but they also have to be on a stable dose for six months. We've had many, many patients that have tried to come into the PROSERA study, but they're not on a stable dose of sotatercept. Physicians and patients are really having to play with dose, whether that be dose reduction, whether that be drug holidays.
The volatility of how sotatercept is being dosed, we think, speaks to the challenge that physicians and patients are having with the therapy because of the side effect profile. As a result, it's really making us feel very bullish about the landscape that we'll launch into in 2027.
Interesting. I heard you say best-in-class efficacy as well as safety. What would the safety or the efficacy profile that you'd hope to demonstrate look like?
I think we have to start with the appropriate benchmark, and it's something that you and I have spoken about, which is if you look at where the investment community is comparing Gossamer or a potential Gossamer outcome in phase III, they're benchmarking us to what sotatercept showed in the STELLAR study, which was roughly a 40-meter improvement in Six-minute walk distance. The current conversation in the clinical community is quite different than what's going on in the investment community. Part of that is that since the Winrevair failure or the safety issues that they've had, there's been a real dialogue as to what drives efficacy with an activ in ligand trap. We know the Winrevair molecule was designed to not touch hemoglobin. We know that the phase III study, STELLAR for sotatercept, had a 1.3 g/dL increase in hemoglobin.
We know from the literature that for every one gram per deciliter increase in hemoglobin, that yields roughly a 25-meter increase in Six-minute walk distance. If you just look at what a hemoglobin-adjusted reality is for sotatercept, the actual mechanistic change that they saw or drive in exercise capacity was probably somewhere anywhere from, again, KOL s hypothesizing, not Gossamer, about 10-15 meters. If we're able to have a 25-meter increase in Six-minute walk, that will be very, very clinically relevant because we were able to achieve that without any increase in hemoglobin, which, as you know, Joe, long-term elevated levels of hemoglobin are not a good thing, and they certainly are not a good thing in PAH patients because, as we've talked about, an increase in your viscosity of your blood makes your right heart work harder. These patients die from right heart failure.
We think the setup for a comparison of an apples-to-apples efficacy parameter, when you remove what hemoglobin does for these patients, will position us to have best-in-class efficacy as well as the best-in-class safety that we've shown through our phase II and the phase III to date.
Okay. Very interesting. Can we talk about what you've done with PROSERA in terms of its design to enroll patients that have the highest likelihood of benefiting?
Absolutely. Why don't you take that, Robert?
Thanks, Joe. Thanks for having us. If we think about lessons learned from the phase II program, one would normally look at that and, if you will, incorporate those learnings into the phase III design, and that's what Gossamer did. In TORREY, recall that we had a less sick patient population. There were a lot of low-risk patients. They were well-managed and also had disease for many years. Importantly, when we looked at the phase II of competitor trials at the time, we had higher Six-minute walk at baseline, a lower pulmonary vascular resistance, and again, lower NT-proBNP and BNP. Again, these patients were in general less sick. We know that we need to have impairment to improve impairment.
With that, we took a look at our phase III design and what we decided to do is that in addition to the traditional, if you will, eligibility criteria of a Six-minute walk and PVR, and our Six-minute walk is 150-475 meters, our PVR is 400 dynes or greater. We incorporated an enrichment strategy using a validated, if you will, risk assessment tool. In this case, it's the REVEAL Lite 2. It's a non-invasive set of parameters that are easily obtained from patients. We use a REVEAL Lite 2 enrichment criteria of greater than or equal to five, which puts that patient in what's known as an intermediate risk category or higher. That's intermediate risk of, if you will, morbidity mortality events. These patients over time have a likelihood, if untreated, will progress in their disease.
We supplemented that as well with some optionality for physicians because we are doing a global study. They can have, if you will, an abnormal NT-proBNP of greater than 300 or just come in, and some of these patients are young women, less comorbidities, and just have the, if you will, hemodynamic impairment, which again leads to their exercise capacity impairment. They could have a hemodynamic impairment of greater than 800 dynes. We are trying to, if you will, get a homogeneous population that has impairment, but doing it through various, if you will, enrichment criteria.
I would just add on to that, Joe, that certainly, and I know we've said this publicly, that at the end of last year, right around the time of the Tufts PAH meeting, we took a look at the baseline characteristics of the first half of the enrolled population. The enrichment strategy is working. The patient population that we had enrolled at that halfway point was as sick or sicker on some of the parameters than what our friends at Merck were able to achieve with STELLAR. I do feel like we are doing everything we possibly can to ensure that seralutinib has the best shot of working in this phase III.
Great. How do you think enrollment has progressed throughout the entire time that you've been recruiting? Can you remind us of your strategy to recruit patients relative to sotatercept's availability here and overseas?
We were very, very thoughtful in the planning, both people, process, and infrastructure. As a benchmark, the sotatercept phase III study was about 65% ex-U.S., 35% U.S. from an enrollment perspective. We wanted to be about 70/30 outside of the United States, with about 55-60% coming from Europe, about 30-40% of that pie coming from Latin America, and then some representation from Asia-Pacific. That has gone very well. We did that because we knew as we were getting into, call it the third inning of the study, that sotatercept would be launched in the United States and that we would have a relative quiet period in the U.S. because we knew patients were being warehoused by physicians for the launch of sotatercept. That, in fact, happened.
As you know, sotatercept is commercially available in the United States and Germany and very limited compassionate use in some other EU countries. The strategy has worked very well because we were able to leverage our infrastructure outside the United States to have the enrollment timelines be met. I think where we've seen some upside surprise is with how strong, especially in the fourth quarter, our enrollment has been in the United States. Now, we still carry a fairly high screen failure rate, which is what you want when you're trying to get ideal patients to be able to move at week 24.
As we've seen the real-world realities of sotatercept, Winrevair, and the liabilities that it's had, we have seen a very different dialogue between physicians and patients in the fourth quarter of last year and the first quarter of this year than we saw, say, a year ago. That has been very, very beneficial for us when it comes to our timelines. Now, our friends at Merck had said in the fourth quarter they saw some seasonality, which was why they had the performance that they did with Winrevair. I would tell you that as we exited the fourth quarter of last year, our screening funnel in the United States had never been larger.
I do think that as physicians are understanding the liabilities of sotatercept, the opportunity to put their patients in a phase III clinical study where safety, efficacy are known has been an advantage for us.
Okay. Interesting. I know that you're enriching enrollment to ensure that patients have enough disease activity that you can register a benefit. Is there any risk of having patients that are too sick in the trial? How should we think about whether there's a sweet spot for this kind of a treatment?
Recall we're not enrolling Functional Class IV patients in our study, so they have to show some modicum of clinical stability, and we have some other guardrails in the eligibility criteria. Again, what we're looking for is those patients that are moving. If you think about it, those in intermediate risk or higher, if they go untreated or, if you will, their treatment is not optimal, they will decline over time. Remember, our study is 48 weeks in duration, double-blind, 24 for Six-minute walk, but 48 weeks for clinical worsening events.
That being said, in terms of the study design, we have that element, but we also know that our drug, based on our phase II results, has meaningful effects in patients who have more impairment. We showed that with the pre-specified analysis from TORREY that the functional class three patients, the patients who had elevated risk, did quite well. I think to complement what Bryan was also saying about the additional interest, the seralutinib story has been evolving over the last year. A year ago, we did not have our open label data out. Recall we did right heart catheterizations at week 72 for the TORREY double-blind patients, which most companies do not look that far out. Most companies would also be happy with the durability of effect. You had your effect at week 24, and it maintained. That is great. We did not just show durability of effect.
We showed with those continued seralutinib patients additional progressive effects beyond week 24. I think once that data got out and, if you will, communicated to the PAH community, especially our investigator network, and remember we're in 31 countries with PROSERA, that resonated with a lot of folks because they could tell their patients, you may see some benefit, and you may see additional benefit the longer you stay on. With that data on the efficacy, we also had our safety and tolerability data. We showed long-term, not just at 72 weeks, but at 144 weeks, that there was no additional, if you will, safety signals or burden or new adverse events, worsening adverse events.
What you saw is what you get in terms of the longer you stay on, you may have additional opportunity to benefit, but no additional, if you will, baggage from long-term side effects. I think that's where sotatercept and seralutinib are showing some differentiation. We may get to the same place efficacy-wise. However, there may be a window of opportunity to treat with sotatercept that gets burdened over time by increasing risk of some safety signals and/or side effects. Whereas with seralutinib, yes, it's a different mechanism of action. You're not going to feel well in two weeks due to the, I'll call it the Tour de France effect with hemoglobin, but long-term, you can stay on it. That's the key because, as you know, we've always looked at this with other PAH therapies.
The key to getting a drug and trying to prevent progression in this disease is starting them early. I believe over time, the community will recognize seralutinib as a drug you could start earlier in the patient's journey, keep them on it for years, and add sotatercept or prostacyclines or whatever you want for symptom relief over time. If we're truly a remodeling agent, this is what you want to do. You want to treat the disease early when there's something still to remodel. That's another message that's starting to resonate with the community as well.
Yeah. To that point, do you have any anatomical data or any other objective biomarker data to show that there's this biological morphological benefit occurring?
We have data that we've already put out in the public domain, which from our TORREY study, recall that we showed with functional respiratory imaging, which is using a standard CT scan looking at the pulmonary vasculature, where we showed we were increasing, if you will, the ratio of small vessels, which we believe is the site of disease, that we've actually restored those vessels in patients treated with seralutinib. We're doing a large sub-study of that in our PROSERA study to validate those results. We believe that will be very strong data. We also showed, if you will, in the TORREY double-blind study, our echocardiographic data where we showed there was, if you will, a maintenance or a protective effect on the right ventricle during the first 24 weeks. Beyond the 24 weeks, the longer you stayed on drug, we actually showed some improvement too.
That data, the clinical data, which has been put out there, plus we have biomarker data that's being presented at various meetings this year to show that we're hitting exactly where we postulated with those underlying pathways of inflammation, proliferation, and fibrosis. Some of the fibrosis data and inflammation data was presented, I think, at the CHEST meeting last year as well. We're targeting those processes, which we believe are in the, if you will, the disease pathophysiology. Again, we believe and we think the data is supporting us as a remodeling agent.
I don't think we can underestimate the power of the imaging data that we have, Joe. A picture's worth a thousand words. When you can show patients and physicians that, in fact, your lung is being revascularized by the use of this therapy in a statistically significant way, we're the only sponsor who has ever done this imaging data. We're the only sponsor who's put out the amount of echo data that we have. At the end of the day, we are able to put out that data. We're able to run that experiment because of our confidence in what seralutinib is doing to the underlying plumbing of the vasculature in the lung. We're the only folks that have done it. We'll continue to do that. It's going to be absolutely part of our phase III study.
We think that differentiation is not only going to help us commercially, but it's going to have implications as we think about going into PH-ILD as a drug that is truly having an impact on the underlying vasculature in the lungs.
Okay. Perfect. That is a great segue for us to talk about PH-ILD. I appreciate that. Can you tell us about the similarities and differences between PH and PH-ILD and why you think seralutinib might work in the latter?
Remember what we're treating in this initial go is a different form of pulmonary hypertension. We're attempting with our PH-ILD program to treat the pulmonary hypertension component of patients with this other, if you will, significant comorbidity of the progressive lung disease. What we've learned from previous development programs is that not all drugs that are successful in treating PAH can, if you will, treat the PH component of chronic lung disease. We believe we have very good preclinical data that we've talked about a little bit. We could probably extrapolate on a little bit. Plus, because we're delivering an inhaled product, we can avoid the problems some drugs have had, especially the vasodilators of VQ mismatch, which we certainly don't want to go there. We don't believe seralutinib has that, if you will, risk associated with it.
If we're treating the underlying mechanisms of the disease with the inflammation, proliferation, and fibrosis, that should be, again, applied to multiple forms of pulmonary hypertension. I think group three is just the start. If we see effects in group three, we can ask other clinical questions of where seralutinib may have some clinical utility.
Our proof of concept was what we did with TORREY. We're addressing the underlying pulmonary hypertension. We do think that through targeting both proliferation, but also through c-KIT and CSF1R, inflammation and underlying fibrosis, we may have an opportunity to actually treat the underlying lung disease as well. That being said, if all we're doing is touching the underlying pulmonary hypertension, we look at what our friends at United are doing with Tyvaso now on a $2 billion run rate. That's a good business if you can do that.
Right. Okay. Speaking of some other companies, Merck recently announced that they're going to be stopping the ZENITH study of the sicker patients who are class three and four. Can you give us your thoughts on what this means, if anything, for Gossamer and seralutinib?
Yeah. You know, the Functional Class IV patients is a smaller patient population. These are people who are relatively immobile on lung transplant lists. I'm very, very happy that Merck was able to stop that study early because that is a patient population where the mortality quite often is imminent. Their ability to step into those sickest patients, albeit the smallest piece of the PAH market, is a wonderful outcome for this patient population. One where, quite frankly, we don't see seralutinib being necessarily a tool because just the sheer number of patients that are functional class two and functional class three patients who, as we have seen from our clinical work, want a therapy that can restore normalcy for life. That's certainly where the vast majority of the wallet is in pulmonary hypertension.
That being said, if you are one of these patients who is refractory to everything and on a transplant list, it's wonderful that that small patient population now has an opportunity to hopefully have Winrevair and sotatercept have an effect, maybe take them off of a transplant list, maybe elevate them back to a functional class 3 patient, or maybe then we can start to treat them with seralutinib. It's wonderful that sotatercept is a rescue med for that sick patient population.
They don't need to be in a study. They just need to be treated.
Yeah.
Yeah. Makes sense. Any thoughts on the discontinuation of the HYPERION study with the less severe patients with two and three disease?
Yeah. It's a great debate that we've been having to understand some of the nomenclature that they use. At the end of the day, what I'll say is sotatercept's a really good drug. We know it has an impact on folks. I think we are anxious to see the data and how that plays out into the real world because ultimately, again, I think the biggest governor on use of sotatercept in healthier patient populations is going to be the liability profile that they have. I think in that patient population where you're trying to give patients the opportunity to have a "normal life," that is where the liabilities and the safety issues can be a real determinant as to what therapy you're going to go on. We come to the table very, very confident with our safety profile.
Can you talk a little bit about maybe the reasons for that? I know you did a lot of work with dosing and the inhaler. Is that a big contributor to the profile that you might be?
I think it is because, again, many of these patients are treated by pulmonologists or they have cardiologists who understand lung function. The ability to train someone to be able to use our inhaled device, which again, is an off-the-shelf device made by a company called Plastiape, used by millions of patients through Sandoz's asthma and COPD franchise. The ability to have both convenience, ease, and not have to have, for example, an injection kit sent to their house every three weeks, we think is a commercial differentiator. As you know, Joe, we also expect to launch in PAH with an improved formulation that takes our puff burden from six puffs twice a day to three puffs twice a day, which again, only we think enhances the commercial viability of seralutinib.
Our partners at Chiesi, who've been in the respiratory business for 85 years, have certainly validated that that will be not only very, very important for commercial implications, but certainly for pricing implications, for example, in the European Union. We are very, very excited with the profile that we'll be bringing forward here over the next couple of years.
Okay. I think we are about out of time, but I think we covered a lot of ground. Thanks so much for the update, gentlemen.
Always a pleasure to be here, Joe. Thank you as always.